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Effects of a G protein-biased mu opioid receptor agonist PZM21 in primates

G 蛋白偏向的 mu 阿片受体激动剂 PZM21 对灵长类动物的影响

基本信息

批准号：
9404668
负责人：
MEI-CHUAN KO
金额：
$ 21.94万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9404668
关键词：
Absence of pain sensation Acute Adverse effects Agonist Analgesics Award Behavioral Behavioral Assay Biological Assay Bradycardia Capsaicin Carrageenan Chemicals Clinical Communities Constipation Data Development Disease Docking Dose Economic Burden Evaluation Future G-substrate GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gastrointestinal Transit Goals Human Hyperalgesia Hypotension Institutes Intervention Intravenous Lead Ligands Light Macaca mulatta Measurement Measures Mediating Medical Medical Economics Mental Depression Modeling Monkeys Morphine Naltrexone Nociceptive Stimulus Opioid Analgesics Opioid Peptide Opioid Receptor Pain Pain management Peptide Receptor Pharmaceutical Preparations Pharmacology Pharmacology Study Phylogenetic Analysis Physical Dependence Physiological Primates Pruritus Public Health Recruitment Activity Research Research Support Risk Rodent Role Safety Scientist Sedation procedure Self Administration Series Side Signal Transduction Societies Structure Symptoms Testing Therapeutic Ventilatory Depression allodynia awake beta-arrestin design experimental study high risk improved mortality mu opioid receptors natural hypothermia nonhuman primate novel opioid use protein activation receptor function scaffold species difference tool virtual

项目摘要

Mu opioid peptide (MOP) receptor agonists such as morphine are the most widely used analgesics for pain management. However, MOP receptor agonist-assoicated abuse liability and mortality lead to mounting medical and economic burdens in the global community. Recent evidence indicates that biased MOP receptor agonists with preferred G protein activation retain analgesic effects, but they are devoid of MOP receptor-mediated side effects. Such compounds have not been studied systemically in non-human primate (NHP) models with translational potential. In this application, we select a newly discovered G protein-baised MOP receptor agonist, PZM21, which will be synthesized by Dr. Yanan Zhang at Research Triangle Institute. A series of NHP experiments will be conducted to evaluate effects of PZM21 in side-by-side comparisons with clinically used MOP receptor agonists following acute and repeated administration. These NHP assays have been designed specifically to reflect the therapeutic (analgesia) and side effects (abuse liability, respriatory depression, constipation, physical dependence, and tolerance) of opioid analgesics. The possibility that drugs with G protein-biased agonism will be effective analgesics with reduced side effects encourages our pharmacological studies of PZM21 in NHP models. Our unique set of physiological and behavioral assays in awake, behaving rhesus monkeys, in combination with the availability of a novel G protein-biased MOP receptor agonist PZM21, sets the breakthrough stage for the identification of safe, non-addictive analgesics in primates and sheds light on future clinical interventions with novel opioid analgesics.

吗啡等阿片肽受体激动剂是目前应用最广泛的镇痛药